Ras drives malignancy through stem cell crosstalk with the microenvironment

Shaopeng Yuan, Katherine S. Stewart, Yihao Yang, Merve Deniz Abdusselamoglu, S. Martina Parigi, Tamar Y. Feinberg, Karen Tumaneng, Hanseul Yang, John M. Levorse, Lisa Polak, David Ng and Elaine Fuchs ()
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Shaopeng Yuan: The Rockefeller University
Katherine S. Stewart: The Rockefeller University
Yihao Yang: The Rockefeller University
Merve Deniz Abdusselamoglu: The Rockefeller University
S. Martina Parigi: The Rockefeller University
Tamar Y. Feinberg: The Rockefeller University
Karen Tumaneng: The Rockefeller University
Hanseul Yang: The Rockefeller University
John M. Levorse: The Rockefeller University
Lisa Polak: The Rockefeller University
David Ng: The Rockefeller University
Elaine Fuchs: The Rockefeller University

Nature, 2022, vol. 612, issue 7940, 555-563

Abstract: Abstract Squamous cell carcinomas are triggered by marked elevation of RAS–MAPK signalling and progression from benign papilloma to invasive malignancy1–4. At tumour–stromal interfaces, a subset of tumour-initiating progenitors, the cancer stem cells, obtain increased resistance to chemotherapy and immunotherapy along this pathway5,6. The distribution and changes in cancer stem cells during progression from a benign state to invasive squamous cell carcinoma remain unclear. Here we show in mice that, after oncogenic RAS activation, cancer stem cells rewire their gene expression program and trigger self-propelling, aberrant signalling crosstalk with their tissue microenvironment that drives their malignant progression. The non-genetic, dynamic cascade of intercellular exchanges involves downstream pathways that are often mutated in advanced metastatic squamous cell carcinomas with high mutational burden7. Coupling our clonal skin HRASG12V mouse model with single-cell transcriptomics, chromatin landscaping, lentiviral reporters and lineage tracing, we show that aberrant crosstalk between cancer stem cells and their microenvironment triggers angiogenesis and TGFβ signalling, creating conditions that are conducive for hijacking leptin and leptin receptor signalling, which in turn launches downstream phosphoinositide 3-kinase (PI3K)–AKT–mTOR signalling during the benign-to-malignant transition. By functionally examining each step in this pathway, we reveal how dynamic temporal crosstalk with the microenvironment orchestrated by the stem cells profoundly fuels this path to malignancy. These insights suggest broad implications for cancer therapeutics.

Date: 2022
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DOI: 10.1038/s41586-022-05475-6

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